title: NFIL3 is a regulator of IL-12 p40 in macrophages and mucosal immunity.
abstract: Regulation of innate inflammatory responses against the enteric microbiota is essential for the maintenance of intestinal homeostasis. Key participants in innate defenses are macrophages. In these studies, the basic leucine zipper protein, NFIL3, is identified as a regulatory transcription factor in macrophages, controlling IL-12 p40 production induced by bacterial products and the enteric microbiota. Exposure to commensal bacteria and bacterial products induced NFIL3 in cultured macrophages and in vivo. The Il12b promoter has a putative DNA-binding element for NFIL3. Basal and LPS-activated NFIL3 binding to this site was confirmed by chromatin immunoprecipitation. LPS-induced Il12b promoter activity was inhibited by NFIL3 expression and augmented by NFIL3-short hairpin RNA in an Il12b-bacterial artificial chromosome-GFP reporter macrophage line. Il12b inhibition by NFIL3 does not require IL-10 expression, but a C-terminal minimal repression domain is necessary. Furthermore, colonic CD11b(+) lamina propria mononuclear cells from Nfil3(-/-) mice spontaneously expressed Il12b mRNA. Importantly, lower expression of NFIL3 was observed in CD14(+) lamina propria mononuclear cells from Crohn's disease and ulcerative colitis patients compared with control subjects. Likewise, no induction of Nfil3 was observed in colons of colitis-prone Il10(-/-) mice transitioned from germ-free to a conventional microbiota. In conclusion, these experiments characterize NFIL3 as an Il12b transcriptional inhibitor. Interactions of macrophages with the enteric microbiota induce NFIL3 to limit their inflammatory capacity. Furthermore, altered intestinal NFIL3 expression may have implications for the pathogenesis of experimental and human inflammatory bowel diseases.
authors.affiliation: Center for Gastrointestinal Biology and Diseases, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Taku
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Matsuoka
authors.forename: Shehzad Z
authors.initials: SZ
authors.lastname: Sheikh
authors.forename: Houda Z
authors.initials: HZ
authors.lastname: Elloumi
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Kamada
authors.forename: Tadakazu
authors.initials: T
authors.lastname: Hisamatsu
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Hansen
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Doty
authors.forename: Scott D
authors.initials: SD
authors.lastname: Pope
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Smale
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Hibi
authors.forename: Paul B
authors.initials: PB
authors.lastname: Rothman
authors.forename: Masaki
authors.initials: M
authors.lastname: Kashiwada
authors.forename: Scott E
authors.initials: SE
authors.lastname: Plevy
mesh_terms: D000818:Animals; D001483:Base Sequence; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018928:Immunity, Mucosal / Q000276:immunology*; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034622:RNA Interference; D012689:Sequence Homology, Nucleic Acid
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D053762:Interleukin-12 Subunit p40; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C497441:Nfil3 protein, mouse; D016753:Interleukin-10; D049452:Green Fluorescent Proteins